7b2ccf9be6667c9033202705dad5c035 ijms-26-05394-v4.pdf 2a70bee3200598e027bb9465576bfe63cda4f606 ijms-26-05394-v4.pdf d6dcd2b40f27afa32b8e6bb63e750dfb326eedfd55be850818039cf58ffa670e ijms-26-05394-v4.pdf Title: Emerging Immunotherapy Targets in Early Drug Development Subject: Immunotherapy has significantly changed the treatment paradigm for solid tumors, with immune checkpoint inhibitors now established in the management of many malignancies. Despite initial success, durable responses remain limited to a subset of patients, often less than 30%, due to both intrinsic and acquired resistance mechanisms. These challenges have prompted the development of next-generation immunotherapies. Recent efforts have expanded the scope of immunotherapy beyond PD-1/PD-L1 and CTLA-4 inhibition, focusing on new immune targets currently under investigation in early phase clinical trials. These include novel immune checkpoint inhibitors, immunomodulators targeting the tumor microenvironment, and bispecific antibodies. This review provides a comprehensive overview of emerging immune targets currently being investigated in early drug development, discussing their mechanisms of action, preliminary clinical outcomes, and potential future directions. Keywords: immunotherapy; phase 1 trial; early drug development; checkpoint inhibitors; bispecific antibodies; tumor microenvironment Author: Daniel Morchón-Araujo, Greta Catani, Oriol Mirallas, Giulia Pretelli, Vicky Sánchez-Pérez, María Vieito, Irene Braña, Ricardo Pujol-Borrell, Elena Garralda and Alberto Hernando-Calvo Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Mon Jun 9 12:49:01 2025 CEST ModDate: Mon Jun 9 12:53:12 2025 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 39 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1619030 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- DORTIW+EURM10 Type 1 Builtin yes yes yes 10 0 ZCVMQM+URWPalladioL-Roma Type 1 Custom yes yes yes 15 0 JNQLNZ+URWPalladioL-Bold Type 1 Custom yes yes yes 21 0 NXBGUU+URWPalladioL-Ital Type 1 Custom yes yes yes 26 0 LEIBBD+PalatinoLinotype TrueType WinAnsi yes yes no 57 0 LEIBBF+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 60 0 LEIBBD+PalatinoLinotype TrueType WinAnsi yes yes no 74 0 KWKPAT+CMSY10 Type 1 Builtin yes yes yes 90 0 CRJHCU+PazoMath-Italic Type 1 Builtin yes yes yes 135 0 MKIRSV+EURM7 Type 1 Builtin yes yes yes 156 0 HQBQWV+VnURWPalladioL Type 1 Custom yes yes yes 204 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-07-08 02:08:20 CEST RepresentationInformation: ijms-26-05394-v4.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-07-07 14:41:49 CEST Size: 1619030 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 873 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Immune Checkpoint Inhibitors Beyond PD-1/PD-L1 and CTLA-4 Destination: section.2 Children: Item: Title: Lymphocyte Activation Gene 3 (LAG-3 and CD223) Destination: subsection.2.1 Item: Title: T-Cell Membrane Protein 3 (TIM-3) Destination: subsection.2.2 Item: Title: T-Cell Immunoreceptor with Ig and ITIM Domains (TIGIT) Destination: subsection.2.3 Item: Title: Other Inhibitory Checkpoints Destination: subsection.2.4 Item: Title: Targeting Co-Stimulatory Pathways Destination: section.3 Children: Item: Title: OX40 Destination: subsection.3.1 Item: Title: 4-1BB (CD137) Destination: subsection.3.2 Item: Title: Other Co-Stimulatory Receptors Destination: subsection.3.3 Item: Title: Cytokine Modulation Destination: section.4 Children: Item: Title: Interleukin-2 (IL-2) Destination: subsection.4.1 Item: Title: Interleukin-15 (IL-15) Destination: subsection.4.2 Item: Title: Other Cytokines Destination: subsection.4.3 Item: Title: Targeting the Tumor Microenvironment Destination: section.5 Children: Item: Title: Depleting Tregs with Anti-CCR8 Therapies Destination: subsection.5.1 Item: Title: Blocking the “Don’t Eat Me” Signal: CD47 Destination: subsection.5.2 Item: Title: Inhibiting TGF- Signaling Destination: subsection.5.3 Item: Title: Targeting Metabolic Pathways Destination: subsection.5.4 Item: Title: Exploring Novel Targets with Bispecific Antibodies Destination: section.6 Item: Title: Current Challenges and Future Directions Destination: section.7 Item: Title: References Destination: section.8 Info: Title: Emerging Immunotherapy Targets in Early Drug Development Author: Daniel Morchón-Araujo, Greta Catani, Oriol Mirallas, Giulia Pretelli, Vicky Sánchez-Pérez, María Vieito, Irene Braña, Ricardo Pujol-Borrell, Elena Garralda and Alberto Hernando-Calvo Subject: Immunotherapy has significantly changed the treatment paradigm for solid tumors, with immune checkpoint inhibitors now established in the management of many malignancies. Despite initial success, durable responses remain limited to a subset of patients, often less than 30%, due to both intrinsic and acquired resistance mechanisms. These challenges have prompted the development of next-generation immunotherapies. Recent efforts have expanded the scope of immunotherapy beyond PD-1/PD-L1 and CTLA-4 inhibition, focusing on new immune targets currently under investigation in early phase clinical trials. These include novel immune checkpoint inhibitors, immunomodulators targeting the tumor microenvironment, and bispecific antibodies. This review provides a comprehensive overview of emerging immune targets currently being investigated in early drug development, discussing their mechanisms of action, preliminary clinical outcomes, and potential future directions. 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